Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity. None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis.